The development of the human cerebral cortex is an orchestrated process involving the generation of neural progenitors in the periventricular germinal zones, cell proliferation characterized by symmetric and asymmetric mitoses, followed by migration of post-mitotic neurons to their final destinations in six highly ordered, functionally specialized layers (2008, Bystron et al., Nature Rev. Neurosci. 9:110-122; 2009, Rakic, Nature Rev. Neurosci, 10:724-735). An understanding of the molecular mechanisms guiding these intricate processes is in its infancy, substantially driven by the discovery of rare mutations that cause malformations of cortical development (2008, Guerrini et al., Trends Neurosci, 31:154-162; 2005, Guerrini, Epilepsia 46 (suppl, 1):32-37; 2001, Guerrini and Carrozzo, Am. J. Med. Genet, 106:160-173; 2001, Mochida and Walsh, Curr. Opin. Neurol, 14:151-1563). Mapping of disease loci in putative Mendelian forms of malformations of cortical development has been hindered by marked locus heterogeneity, small kindred sizes and diagnostic classifications that may not reflect molecular pathogenesis.
Malformations of cortical development are a diverse group of often devastating structural brain disorders reflecting deranged neuronal proliferation, migration or organization. Application of traditional mapping approaches have proved to be particularly challenging for gene discovery in these syndromes, where kindreds with a single affected member are most common, linkage studies support high locus heterogeneity and recent genetic findings have fundamentally challenged previous diagnostic nosology Guerrini et al, Trends Neurosci. 31:154-162; 2001, Barkovich et al., Neurology 57; 2168-2178; 2005, Barkovich et al., Neurology 65:1873-1887). Whole-exome sequencing using next generation platforms (2009, Choi et al., Proc. Natl Acad. Sci. USA 106:19096-19101; 2010, Ng et al., Nature Genet. 42:30-35; 2009, Ng et al., Nature 461:272-276) can markedly improve gene discovery efforts in these situations.
There is a need in the art for assays for detecting recessive mutations in genes involved in cortical development in both carrier subjects and affected subjects. The present invention addresses this need in the art.